Utility of synthetic MRI in predicting pathological complete response of various breast cancer subtypes prior to neoadjuvant chemotherapy.

AIM: To evaluate the usefulness of synthetic magnetic resonance imaging (MRI) performed before the initiation of neoadjuvant chemotherapy (NAC) in predicting whether breast cancers can achieve a pathological complete response (pCR) after the completion of NAC. MATERIALS AND METHODS: This retrospective study investigated 37 consecutive patients with 39 breast cancers (pCR: 14, and non-pCR: 25) who underwent dynamic contrast-enhanced (DCE)-MRI and synthetic MRI before the initiation of NAC. Using synthetic MRI images, quantitative values (T1 and T2 relaxation times, proton density [PD] and their standard deviations [SD]) were obtained in breast lesions, before (Pre-T1, Pre-T2, Pre-PD, SD of Pre-T1, SD of Pre-T2, SD of Pre-PD) and after (Gd-T1, Gd-T2, Gd-PD, SD of Gd-T1, SD of Gd-T2, SD of Gd-PD) contrast agent injection. The aforementioned quantitative values and several morphological features that were identified on DCE-MRI were compared between pCR and non-pCR. RESULTS: Multivariate analyses revealed that the SD of Pre-T2 (p=0.038) was significant and was an independent predictor of pCR, with an area under the receiver operating characteristics curve of 0.829. The sensitivity, specificity, and accuracy of the SD of Pre-T2 with an optimal cut-off value of 11.5 were 71.4%, 80%, and 76.3%, respectively. CONCLUSIONS: The SD of Pre-T2 obtained from synthetic MRI was used successfully to predict those breast cancers that would achieve a pCR after the completion of NAC; however, these results are preliminary and need to be verified by further studies.

Bicalutamide 80 mg combined with a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in advanced prostate cancer: findings from a phase III randomized, double-blind, multicenter trial in Japanese patients.

To compare combination therapy with bicalutamide 80 mg and a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A alone in Japanese men with untreated advanced prostate cancer. A total of 205 patients with stage C/D prostate cancer were randomized to either LHRH-A+once-daily oral bicalutamide 80 mg or placebo. Primary study variables have been reported previously. Secondary variables included: time to achieve prostate-specific antigen < or = 4 ng/ml, time-to-treatment failure (TTTF), time-to-disease progression (TTP), overall survival (OS), adverse events and adverse drug reactions. Following combination therapy with bicalutamide 80 mg, there were significant (P<0.001) advantages over LHRH-A alone in terms of TTTF and TTP, but the difference in the interim OS was not statistically significant. First-line combination therapy with bicalutamide 80 mg in Japanese patients with advanced prostate cancer offers significant benefits over LHRH-A alone, with respect to TTTF and TTP. Follow-up for OS continues.

Laparoscopic radical retropubic prostatectomy combined with approaches through a small open incision.

PURPOSE: The laparoscopic technique is now applied to radical prostatectomy. However, even in laparoscopic prostatectomy, we need a small open wound to remove the prostate from the abdomen. We have developed a modified technique of extraperitoneal laparoscopic radical prostatectomy, exploiting this small open wound as a route for surgical manipulations as well. Here, we described our technique and its initial outcomes. PATIENTS AND METHODS: An extraperitoneal retropubic space was developed with finger manipulations through a 3- to 5-cm long suprapubic incision. Three or four trocar ports were set up. A specially designed abdominal wall-lifter was applied to create an endoscopic working space. The surgeons worked using open or endoscopic manipulations through the suprapubic incision or the trocar ports. From October 2000 to August 2001, 11 patients with prostate cancer underwent this surgery. RESULTS: We completed surgery endoscopically without major complications except in one case in which we could not identify a bleeding source. Surgical time ranged from 229 to 469 min. Blood loss ranged from 550 to 3797 ml including urine spilled in the surgical field. Urinary continence returned in 10 cases at 1 to 8 months after surgery. One patient still needed pads at 3 months after surgery. CONCLUSION: Our technique allowed us to avoid insufflation of the abdomen with gas and intraperitoneal surgical intervention that are disadvantages of conventional laparoscopic prostatectomy, offering the same advantages as conventional laparoscopic prostatectomy.

[Pneumatosis intestinalis after allogeneic bone marrow transplantation for acute lymphocytic leukemia].

A 45-year-old man was diagnosed as having acute lymphocytic leukemia (ALL) in February 1997. Complete remission was achieved by chemotherapy, and allogeneic BMT from his HLA-identical sister was performed on November 13, 1997. He developed acute GVHD (grade II), but quickly recovered after methyl-PSL pulse therapy. On June 5, 1998--day 202 after BMT--abdominal pain developed. X-ray and CT examinations showed pneumatosis intestinalis, pneumoperitoneum, pneumomediastinum and abdominal free air. We performed oxygen administration and methyl-PSL pulse therapy, and this quickly improved the symptoms. Corticosteroid and chronic GVHD were thought to be the causative factors of pneumatosis intestinalis in this case. Although pneumatosis intestinalis is relatively rare, it is one of the important potential complications that can occur after allogeneic BMT.

Histopathologic analysis of angiogenic factors in localized renal cell carcinoma: the influence of neoadjuvant treatment.

BACKGROUND: This study was conducted in order to clarify whether histopathologic analysis of factor thymidine phosphorylase (TP) and Factor VIII could be a useful predictor of postoperative recurrence in localized renal cell carcinoma. Therefore, the relationship between tumor infiltrated lymphocytes (TIL) and both TP and Factor VIII was studied. METHOD: Of the 71 patients who underwent surgery, 54 patients had no neoadjuvant therapy (group 1), 10 patients were preoperatively administered IFN-gamma (group 2), and the remaining seven patients preoperatively received IFN-gamma and transarterial embolization (group 3). Both TP and Factor VIII immunostaining were performed on formalin-fixed, paraffin-embedded archival tissue from 71 renal cell carcinoma specimens, while TIL immunostaining was performed on frozen sections. Positive immunostaining was quantitatively scored by a computer-assisted digital image analysis. For TIL, positive results were semiquantitatively scored. RESULTS: A significant difference in the recurrence-free rate was recognized for Groups 1, 2 and 3 (P < 0.05). Therefore, the median TP-positive rate (PR), VIII-PR, number of microvessels and positive mean vascular area levels were investigated, between the recurrence cases (n = 6) and the recurrence-free cases (n = 11). Only the TP-PR levels showed a significant difference among them (P = 0.044). In regards to the neoadjuvant cases, a significant correlation was observed between both VIII-PR and CD4 (r = 0.815) as well as between VIII-PR and CD11b (r = 0.756). CONCLUSION: There was no clear evidence that the neoadjuvant treatment would increase the recurrence-free survival in patients with localized renal cell carcinoma. TP-PR might be a predictor of postoperative recurrence in patients with localized renal cell carcinoma.

Genetic heterogeneity of surgically resected prostate carcinomas and their biopsy specimens is related to their histologic differentiation.

BACKGROUND: In human prostate carcinogenesis, many genetic analyses including conventional loss of heterozygosity (LOH) studies and microsatellite LOH analyses using the polymerase chain reaction method have revealed frequent LOH events at specific regions on chromosomes 3p, 7q, 8p, 10q, 16q, 17q, and 18q. METHODS: Using the laser-captured microdissection method, the authors extracted genomic DNA from 23 cases of prostate carcinomas including 59 different lesions and 8 biopsy specimens. Using (32)P-labeled primers, the authors analyzed six microsatellite loci (D3S647, D3S1228, D7S522, D8S137, NEFL, and D10S190) at which frequent LOH events have been reported. RESULTS: Of 10 cases in which the authors found LOH at any of the loci, 8 cases showed a heterogeneous LOH pattern. In four cases, the authors also found replication error (RER) at some of the loci examined. There was no significant relation between histologic differentiation and frequency of LOH or RER events. The overall LOH rate was found to be significantly lower in foci at classification pT2 (1 of 28 foci, 3%) compared with those at classification pT3 (13 of 44 foci, 30%). In pT3 samples, LOH events in extraglandular foci (9 of 23 foci, 39%) tended to be more frequent compared with those in intraglandular foci (8 of 41 foci, 20%). The patterns of LOH events in biopsy specimens correlated well with those in foci from surgical material showing the same histologic characteristics. CONCLUSIONS: Prostate carcinoma is a genetically multicentric carcinoma, and the genetic heterogeneity is well correlated with histologic differentiation. The frequency of LOH events increased according to the degree of tumor progression.

Lack of allelic exclusion and isotype switching in B cell chronic lymphocytic leukemia.

Two rearranged bands of the IgH gene were detected in a case with B cell chronic lymphocytic leukemia (B-CLL). The expressed VH gene was only VH1 with no somatic mutations in IgM and IgD. The expressions of C mu, C delta, and C gamma were detected by reverse transcription of RNA followed by the polymerase chain reaction (RT-PCR). Sequence analysis of the CDR3 regions of each PCR reaction product showed that the sequence of one rearranged allele was identical to those of the expressed VH1 gene, C mu and C delta, and the sequence of another rearranged allele was identical to that of C gamma. However, none of the expressed VH genes was detected in IgG. These findings suggest that this is a case of B-CLL lacking allelic exclusion and undergoing a class switch of one allele with the incomplete expression of the VH gene.

Morphometric analysis, at electron microscope level, combined with hormone assay of nonfunctioning adrenocortical adenomas: comparison with aldosterone-producing adenomas.

We performed electron microscopic studies of eight nonfunctioning adrenocortical adenomas (NFA) and nine aldosterone-producing adenomas (APA) obtained from surgical specimens. A comparison of these two types of adenomas was conducted by morphometric analysis of random electron micrographs. The organelles measured included mitochondria (M), smooth-surfaced endoplasmic reticulum (SER), rough-surfaced endoplasmic reticulum (RER), lipid vacuoles (LV), and lysosomes (Ly). The content of steroid hormones, including 17-alpha hydroxyprogesterone (17-OHP), aldosterone (Ald), and other steroid hormones, was measured in adenoma tissue from six NFA and eight APA. The percentages of the areas of the organelles M, SER, and RER per total cell area in the NFA were significantly lower than those in the APA. The average content of Ald in adenoma tissues in APA was markedly higher than that in the NFA, while the mean content of 17-OHP in the NFA was significantly higher than that in APA. In conclusion, NFA are morphometrically characterized by a reduction in organelles such as M, SER, and RER, compared with findings in APA. From the quantitative analysis of steroid hormones, it was suggested that NFA produce more precursor substances with less hormone activity than APA and that steroidgenesis in NFA is shifted to a glucocorticoid pathway, as indicated by the elevated 17-OHP concentration.

Differential expression of three types of nitric oxide synthase in both infarcted and non-infarcted left ventricles after myocardial infarction in the rat.

In the present report we investigated the differential expression of three types of nitric oxide synthase (NOS) in the left ventricle after myocardial infarction in rats. One, 3, 7, 14, 28 and 56 days (n=6-12 for each group) after ligation of a coronary artery, tissue samples were obtained from infarcted and non-infarcted tissues. The mRNA and protein levels of neuronal (n) NOS, endothelial (e) NOS and inducible (i) NOS were sequentially determined by semi-quantitative reverse transcription-polymerase chain reaction and Western blotting. Progressive left ventricular dilatation and gradual reduction in fractional shortening were confirmed by echocardiography. The expression levels of nNOS were significantly increased 1, 3 and 7 days post-infarct compared to those of sham-operated rats in both the infarcted (P<0.01) and non-infarcted regions (P<0.01). Immunohistochemical analysis showed that nNOS was localized in nerve fibers in the left ventricle and that the number of positive fibers after myocardial infarction had increased compared to that in sham-operated rats. With regard to eNOS, no significant changes in expression levels were detected between infarcted hearts and sham-operated controls. The level of iNOS expression peaked three days post-infarct and then decreased in the infarcted tissue, whereas it increased one day post-infarct, peaked at 14 and 28 days post-infarct and was still elevated in the chronic stage in the ventricular septum. iNOS immunoreactivity was detected in spared cardiomyocytes and macrophages in the infarcted region, and in cardiomyocytes in the ventricular septum. The expressions of three types of NOS were differentially regulated and iNOS produced in the non-infarcted region may contribute to the progression of heart failure after myocardial infarction in rats.

[MALT lymphoma producing IgG-kappa type M-protein].

A 72-year-old woman, who has been administered prednisolone and azathioprine with diagnoses of idiopathic thrombocytopenic purpura (ITP) and autoimmune hepatitis (AIH), underwent a complete medical examination because of monoclonal gammopathy (IgG-kappa). Tumors were found in the ileum and descending colon. Pathological examination of biopsy specimens suggested a diagnosis of marginal zone B-cell lymphoma of the MALT type with a high-grade component. Flow cytometric analysis by two-color staining revealed that the neoplastic B cells expressed CD38, CD19, IgG and kappa, but not CD5 or CD10. There were no abnormal plasma cells in bone marrow smears. The patient achieved complete remission after receiving three cycles of THP-COP chemotherapy, which resulted in a decrease of the IgG level to within the normal range. These findings indicated that monoclonal IgG-kappa might be produced by lymphoma cells. However, the relationship of the immunosuppressive agents to the pathogenesis of the MALT lymphoma remains to be clarified.

Cytoreductive surgery with liver-involved renal cell carcinoma.

The purpose of this study was to demonstrate the benefits of cytoreductive surgery for renal cell carcinomas that also involve the liver. Between 1994 and 1997, four patients with renal cell carcinoma with liver involvement were surgically treated with nephrectomy and hepatectomy. Two of them underwent a simultaneous hepatectomy and nephrectomy (group 1), and the remaining two patients underwent a hepatectomy after a nephrectomy and had a diagnosis of postoperative recurrence (group 2). Two patients, one from each group, died of multiple bone metastasis and lung metastasis 30 months and 12 months after the hepatectomy; the second patient from group 1 died 40 months after the first operation due to gastrointestinal hemorrhaging. The second patient from group 2 displayed no evidence of recurrence 18 months after the second surgical procedure. The survival rates for these patients were 66% and 33% at 1 and 3 years, respectively. Autopsy studies revealed that one patient from group 2 had a local recurrence in the liver while the other two patients from group 1 did not. Our results suggested that a progressive approach may therefore be useful for patients demonstrating renal cell carcinoma where there is liver involvement.

Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary.

Loss of heterozygosity (LOH) at locus 10q23.3 and mutation of the PTEN tumor suppressor gene occur frequently in both endometrial carcinoma and ovarian endometrioid carcinoma. To investigate the potential role of the PTEN gene in the carcinogenesis of ovarian endometrioid carcinoma and its related subtype, clear cell carcinoma, we examined 20 ovarian endometrioid carcinomas, 24 clear cell carcinomas, and 34 solitary endometrial cysts of the ovary for LOH at 10q23.3 and point mutations within the entire coding region of the PTEN gene. LOH was found in 8 of 19 ovarian endometrioid carcinomas (42.1%), 6 of 22 clear cell carcinomas (27.3%), and 13 of 23 solitary endometrial cysts (56.5%). In 5 endometrioid carcinomas synchronous with endometriosis, 3 cases displayed LOH events common to both the carcinoma and the endometriosis, 1 displayed an LOH event in only the carcinoma, and 1 displayed no LOH events in either lesion. In 7 clear cell carcinomas synchronous with endometriosis, 3 displayed LOH events common to both the carcinoma and the endometriosis, 1 displayed an LOH event in only the carcinoma, and 3 displayed no LOH events in either lesion. In no cases were there LOH events in the endometriosis only. Somatic mutations in the PTEN gene were identified in 4 of 20 ovarian endometrioid carcinomas (20.0%), 2 of 24 clear cell carcinomas (8.3%), and 7 of 34 solitary endometrial cysts (20.6%). These results indicate that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma and clear cell carcinoma of the ovary.

Facial nerve repair using a collagen conduit in cats.

We evaluated facial nerve regeneration using a collagen tube as a nerve conduit in five cats. In three 5 mm of the facial nerve were resected, a collagen tube was implanted, and a 5 mm segment of the opposite facial nerve was resected, reversed 180 degrees, and sutured back as an autologous nerve graft. In one a collagen tube was implanted on one side, and in the remaining one a 5 mm nerve segment was reversed. Histological, electrophysiological, and horseradish peroxidase labelling examinations were carried out 4-24 weeks postoperatively. Histological study showed that the nerve was well vascularised and regenerated. Electrophysiological examination confirmed the recovery of evoked electromyograms through to the regenerated axons. Horseradish peroxidase examination also confirmed restoration of the whole facial nerve. The collagen tube is an efficient nerve conduit.

[Immunohistochemical study of p53 and Ki-67 antigen expression in bladder carcinoma].

We examined the relationship between the expression of mutant p53 and Ki-67 antigens in urinary bladder transitional cell carcinoma and the pathological and clinical findings. Tissues were obtained from 28 patients with bladder carcinoma who underwent total or partial cystectomy. An ABC immunostaining method and two primary antibodies (DO-7 and MIB-1 antibodies) were used. The percentages of p53 and Ki-67 antigen-positive cells to the total number of cells were regarded as the p53 and Ki-67 labeling indices (LI) respectively. There were no statistically significant correlations between p53 LI and the histological grade or stage, although p53 LI increased slightly in the high grade and high stage group. There was a statistically significant correlation between Ki-67 LI and the histological grade and stage (p < 0.05). The correlation between p53 LI and Ki-67 LI was linear. Some cases had a p53 LI below the mean even though the Ki-67 LI was higher. The clinical course was characteristic of superficial bladder carcinoma initially, but progressed to invasive bladder carcinoma over the next several years. These results suggest that even cases initially diagnosed as superficial bladder carcinoma with a low p53 LI may progress to invasive bladder carcinoma in subsequent years. Therefore, it is important that the patient be followed-up.

Experimental replacement of the thoracic esophagus with a bioabsorbable collagen sponge scaffold supported by a silicone stent in dogs.

We manufactured an esophageal prosthesis made of a collagen sponge supported by an inner silicone tube. The collagen was derived from porcine skin and was crosslinked by dehydrothermal treatment. We implanted our prosthesis in nine dogs after resecting a 5 cm length of the thoracic esophagus. Intravenous hyperalimentation was performed for 4 weeks after the surgery. After 29 days, the inner silicone tube was removed endoscopically and oral feeding was restarted immediately. All nine dogs survived more than 1 month, and three of the nine dogs survived for more than 1 year. Endoscopically, the luminal surface of the regenerated esophagus was covered with a lustrous, smooth mucosa, but stenosis was observed in the midregion of the regenerated esophagus. Microscopically, no foreign material remained at the reconstructed site 1 month after surgery; the collagen sponge was absorbed and replaced by host tissue. Complete epithelization was observed within 3 months. Regeneration of the lamina muscularis mucosae, esophageal glands, and skeletal muscle were observed near the anastomoses. Our artificial esophagus holds promise for esophageal reconstruction in a clinical setting, even in the thorax.

Intrathoracic esophageal replacement in the dog with the use of an artificial esophagus composed of a collagen sponge with a double-layered silicone tube.

OBJECTIVES: Intrathoracic esophageal replacement with an artificial esophagus is considered difficult. We attempted to replace the intrathoracic esophagus with an artificial esophagus composed of a collagen sponge with a double-layered silicone tube and examined the state of host tissue regeneration. METHODS: A 5-cm long gap was created in the intrathoracic esophagus in 9 dogs and repaired by interposition of our prosthesis. The dogs were fed only by intravenous hyperalimentation for 28 days. The silicone tube was removed at 29 days after the operation, and oral feeding was reintroduced. RESULTS: One dog was put to death at each of the following times: 1, 2, 3, 3, 6, 12, and 24 months after the operation. One dog is still surviving without problems after more than 26 months. One dog died of malnutrition at 10 months. In all dogs, the host regenerated tissue had replaced the resulting gap at the time of silicone tube removal. The mucosa had fully regenerated within 3 months and the glands within 12 months. The process of stenosis and shrinkage was complete within 3 months and did not advance thereafter. The lamina muscularis mucosae were observed as islets of smooth muscle within 12 months. Although the skeletal muscle regenerated close to the anastomoses, it did not extend to the middle of the regenerated esophagus even after 24 months. CONCLUSIONS: Use of a collagen sponge with a double-layered silicone tube was shown to be feasible even in the thorax and to allow the regenerated host tissue, consisting of the mucosa, glands, and lamina muscularis mucosae, to replace the esophageal gap.

Replacement of the tracheobronchial bifurcation by a newly developed Y-shaped artificial trachea.

We have previously reported on a straight artificial trachea developed by our group that can be applied to the cervical and thoracic trachea. In this study, a new Y-shaped artificial trachea was designed and adapted for experimental replacement of defective tracheal bifurcations in 20 dogs. The Y-shaped Marlex mesh tube was reinforced with a polypropylene spiral and coated with collagen made from porcine skin. This coating process makes the prosthesis biocompatible and airtight. Replacement of the tracheobronchial bifurcation was performed through a right thorachotomy, and omentopexy was added in all 20 dogs. Six of the 20 dogs have survived. The causes of death of the other 14 dogs were obstruction of the main bronchus (one dog), omental necrosis (three dogs), and air leakage from the prostheses and suture points (10 dogs). In all six surviving dogs, the artificial tracheas are covered with regenerated tissue and there is no evidence of stenosis or dehiscence. These results indicate that the prosthesis can be effective and safe in the long-term; however, air leakage from the prosthesis is a serious complication. Therefore, a better method is needed to make the prosthesis airtight to improve the postoperative result.

Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells.

A mitogen for growth-arrested cultured bovine aortic smooth muscle cells was purified to homogeneity from the supernatant of cultured human umbilical vein endothelial cells by heparin affinity chromatography and reverse-phase high performance liquid chromatography. This mitogen was revealed to be tissue factor pathway inhibitor-2 (TFPI-2), which is a Kunitz-type serine protease inhibitor. TFPI-2 was expressed in baby hamster kidney cells using a mammalian expression vector. Recombinant TFPI-2 (rTFPI-2) stimulated DNA synthesis and cell proliferation in a dose-dependent manner (1-500 nM). rTFPI-2 activated mitogen-activated protein kinase (MAPK) activity and stimulated early proto-oncogene c-fos mRNA expression in smooth muscle cells. MAPK, c-fos expression and the mitogenic activity were inhibited by a specific inhibitor of MAPK kinase, PD098059. Thus, the mitogenic function of rTFPI-2 is considered to be mediated through MAPK pathway. TFPI has been reported to exhibit antiproliferative action after vascular smooth muscle injury in addition to the ability to inhibit activation of the extrinsic coagulation cascade. However, structurally similar TFPI-2 was found to have a mitogenic activity for the smooth muscle cell.

Biodegradation and tumorigenicity of implanted plates made from a copolymer of epsilon-caprolactone and L-lactide in rat.

Flat plates made from a copolymer of epsilon-caprolactone and L-lactide (P-CL-LA) [50:50 (w/w), molecular weight 1.62 x 10(5); 20 x 10 x 1 mm size] were subcutaneously implanted into 50 young, male Wistar rats (P-CL-LA group). After 24 months the plates had become a mass of small pieces, which were concentrated in an area of 3 x 2 x 1 mm. For comparison, 50 rats were implanted with medical-grade polyethylene plates (PE group) while another set of 50 rats was subjected to the same operation but without an implant (Sham Op group). Tumors arose in 25 rats from the P-CL-LA group: 24 were malignant mesenchymal tumors at the implant sites. In the PE group, tumors appeared in 16 rats (14 at the implant sites and two ectopically). The average tumor latency was 578+/-84 days in the P-CL-LA group and 452+/-102 days in the PE group. There was no difference in tumor incidence between the P-CL-LA and PE groups (p < 0.05). In the Sham Op group, two malignant tumors appeared over 2 years. Pathologically, these induced tumors arose from the inflammatory cells surrounding the degrading fragments of P-CL-LA within the tissue capsule. This indicates that relatively slowly degrading material can induce malignant tumors at a similarly high rate to nonabsorbable medical grade PE, at least in this animal model.